Many of today's medical diseases can be attributed directly or indirectly to problems with apoptosis—a programmed cell-suicide mechanism. Disorders in which defective regulation of apoptosis contributes to disease pathogenesis or progression can involve either cell accumulation, in which cell eradication or cell turnover is impaired, or cell loss, in which the cell-suicide program is inappropriately triggered. Identification of the genes and gene products that are responsible for apoptosis, together with emerging information about the mechanisms of action and structures of apoptotic regulatory and effector proteins, has laid a foundation for the discovery of drugs, some of which are now undergoing evaluation in human clinical trials.
Typically, one thinks of cell death as being a pathological phenomenon, but in fact, each second nearly one million cells commit suicide in the adult human body. In an average day, we produce, and in parallel eradicate, −60×109 cells which represents a mass of cells equivalent to an entire body weight on an annual basis. This massive flux of cell birth and death occurs in the self-renewing tissues of the body (skin, gut, bone marrow and sex organs), providing mechanisms for rapidly regulating cell numbers by controlling the rates of both input and elimination. Physiological cell death has important roles in a wide variety of normal processes, ranging from fetal development to ageing, and including: immune system education, for which potentially autoreactive cells are eliminated; defense against viruses, for which altruistic cell suicide can deny viral replication within a host; tissue homeostasis, for which cell production is offset by commensurate cell eradication, thereby ensuring appropriate total cell numbers in vivo; and many aspects of reproductive biology.
Programmed cell death is vital to the existence of virtually all organisms, As a result, knowledge about programmed cell-suicide mechanisms can have broad ramifications for devising strategies for protecting crops, interfering with insect and parasite life cycles, tissue engineering and ex vivo cell production, and the development of human therapeutics. Physiological or programmed cell death generally occurs by apoptosis and defects in the physiological pathways for apoptosis have a role in many diseases. A reasonable estimate is that either too little or too much cell death contributes to half of the main medical illnesses for which adequate therapy or prevention is lacking. Consequently, great interest has emerged in devising therapeutic strategies for modulating the key molecules that make life-or-death decisions in cells.
Apoptosis is generally caused by proteases known as “caspases”. Caspases constitute a family of intracellular cysteine proteases that cleave substrates at aspartic acid (Asp) residues. Produced initially as inactive zygomens, caspases are triggered into action generally as a result of their proteolytic processing at conserved Asp residues. Because caspases both cleave their substrates at Asp residues and are also activated by proteolytic processing at Asp residues, these proteases can collaborate in proteolytic cascades, in which caspases activate themselves and each other. Within these cascades, caspases can be positioned as downstream effectors of apoptosis.
U.S. Pat. No. 6,004,794 discloses isolated nucleic acids encoding a human serine protease PSPI, protein obtainable from the nucleic acids, recombinant host cells transformed with the nucleic acids, oligonucleotides and primer pairs specific for PSP1 polymorphisms and use of the protein and nucleic acid sequences. This patent thus discloses the Omi/HtrA2 which has been identified as a mitochondrial apoptotic serine protease that also disrupts the inhibition of apoptosis protein-caspase interaction.
Since the Omi/HtrA2 is present in all mammalian cells and by its activity of disrupting the inhibition of the “apoptosis protein-caspase interaction” decreases the cell lifetime, it would be most important to discover an inhibitor of the adverse activity of Omi/HtrA2 and homologous proteins.